Molecular Pathology of Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer is a rare, autosomal dominant hereditary cancer syndrome associated with germline mutations in CDH1 in which 60% 80% of affected individuals develop advanced diffuse gastric cancer, many as young adults. At clinical presentation, ~90% of these malignancies represent advanced, surgically incurable disease. As such, pre-symptomatic identification of germline CDH1 mutation carriers followed by early prophylactic total gastrictomy is the sole effective management strategy available. DNA sequence analysis of the CDH1 gene to identify the affected germline allele is the diagnostic standard of care; however, CDH1’s relatively high frequency of polymorphisms and the limited amount of experience available regarding them dictate that many identified variants are, as yet, of unknown clinical significance. Given the dramatic consequences of inappropriately offered or withheld treatment, careful clinical selection of at-risk individuals is critical. To facilitate this, multiple groups have published screening criteria recommendations, and while there is disagreement regarding the optimal diagnostic approach, the most widely-used overlap to a considerable degree.